Drug inhibitors that target components of the mitogen-activated protein kinases (MAPK) signaling pathway show clinical efficacy in a variety of cancers, particularly those bearing mutations in the BRAF protein kinase. Both RAF and MEK kinase inhibitors are approved for single-agent use in advanced metastatic BRAF mutant melanoma, and the combination of dabrafenib and trametinib is currently undergoing Food and Drug Administration (FDA) review for this indication. Either alone or in combination, BRAF and MEK inhibitors show variable activity in other cancers, with promising efficacy in BRAF mutant thyroid and lung cancer, as well as possible marginal activity in BRAF mutant colorectal cancer.
Varying patterns of clinical efficacy are seen with BRAF and MEK inhibitors. Both the extent and penetrance of initial tumor regression, as well as duration of response before disease progression, varies uniquely according to each drug class when given alone, or when administered in either sequential or concurrent combination strategies. To date, concurrent dabrafenib and trametinib combination therapy appears to be the preferred intervention for BRAF mutant melanoma.
As with other targeted therapies, patterns of disease response to RAF and MEK inhibitors appear to be influenced by the intrinsic genetic heterogeneity present in the cancers where the drugs are used. For instance, it has been shown that certain genetic alterations, including PTEN and other changes that activate the PI3K cell growth signals, may predict a poor initial response, and/or relatively rapid progression, in BRAF mutant melanoma treated with the RAF inhibitor vemurafenib. Likewise, direct mutations in MEK gene loci appear to emerge in tumors that have progressed following either BRAF, MEK or combined drug treatment. Several additional examples, from RAS and RAF gene amplification and splicing mutations, suggest that acquired drug resistance is produced when oncogenic pleiotropy encounters the selective pressure of targeted drug treatment.
Therefore, novel targeted agents would ideally inhibit diverse nodes of oncogenic pathways, and also be effective in combinations by inducing a burden of selective pressure that exceeds the adaptive capacity of diverse cancer genomes. The present application is directed to meeting, inter alia, the need for novel targeted agents.